Regulation of the aging by calorie restriction: Implications of mitochondrial retrograde signals

卡路里限制(CR)可能通过调节线粒体功能发挥抗衰老作用。我们先前报道，CR上调线粒体蛋白，包括细胞色素C氧化酶(COX)的一个亚单位Cox6b1。为了研究Cox6b1在线粒体中的功能作用，我们利用Cox6b1过表达的细胞或基因敲除细胞进行了体外实验。这些结果表明，Cox6b1通过组装COX超复合体来增强线粒体呼吸，从而介导CR的某些效应，例如，抗逆性。ROS的同时产生可以通过几种机制来阻止，包括NRF2的激活。我们还发现，抑制Cox6b1的上游信号分子糖原合成酶激酶(GSK)-3b可以增加Cox6b1的蛋白表达。因此，我们证实CR增加了小鼠肝脏中GSK-3b的磷酸化，GSK-3b是其非活性形式。本研究支持CR的有丝分裂兴奋假说。

Calorie restriction (CR) may exert anti-aging effects by modulating mitochondrial functions. We previously reported that CR upregulated mitochondrial proteins, including Cox6b1, a subunit of cytochrome c oxidase (Cox). To investigate the functional roles of Cox6b1 in mitochondria, we conducted in vitro experiments using Cox6b1-overexpressing cells or knockdown cells. The findings suggest that Cox6b1 mediates some of the effects, e.g., stress resistance, of CR by enhancing mitochondrial respiration via the assembly of Cox supercomplexes. The simultaneous generation of ROS may be prevented by several mechanisms, including Nrf2 activation. We also found that inhibition of glycogen synthase kinase (GSK)-3b, a putative upstream signaling molecule for Cox6b1, increased Cox6b1 protein expression. Accordingly, we confirmed that CR increased phosphorylated GSK-3b, its inactive form, in the mouse liver. The present study supports the mitohormesis hypothesis of CR.